This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Ross P. Carlson is the PL on the 'Systems Biology of Host-Pathogen Interaction'project. Dr. Carlson is constructing pathogen metabolic models, perform elementary flux mode analysis, as well as design, run, and analyze chemostat experiments. Dr. Carlson will oversee a post-doctoral research associate and the graduate student. The Post-doctoral research associate will build and refine metabolic models, perform elementary modes analysis with data mir and analyze chemostat experiments as well as perform and analyze proteomic analysis of experimental samples. The post-doc will also aid in the supervision of the graduate student. The Graduate student will start in the second year of the project. The graduate student will run analyze, and optimize chemostat cultures, make medium and other reagents, order supplies, care for cultures and maintain equipment. The metabolic basis of pathogen responses to the host immune system is poorly understood. It is hypothesized that a systems analysis of host-pathogen interactions will reveal, explain, and quantify metabolic adaptations critical for pathogenicity. A systems-based understanding of host-pathogen interactions promises to facilitate the development of novel therapeutic strategies for disease treatment with increased specificity and reduced side-effects. The host-pathogen research will integrate proteomic analysis of enzyme levels and activities and quantitative metabolic flux analysis with a mathematically defined, computerized framework to study pathogen virulence mechanisms and host defense mechanisms. This is a "bottom-up" systems biology project that aims to: 1) identify the critical components of the systems by constructing and analyzing in silico metabolic models of the pathogens Escherichia coli and Candida albicans and the host macrophage cells, 2) study how the components work through computer simulations and in vitro experiments following pathogens adapting to stresses associated with infection, and 3) determine how the components can work together to accomplish the biological mechanism by measuring and modeling the simultaneous metabolic adaptations of both host and pathogen during infection. Previously reported transcriptome studies of pathogens engulfed in phagosomes provide an experimental footing for the proposed work, however;the correlation between mRNA and protein levels is often low and in some cases, even negative. In addition, protein activities are often altered by post-translational modifications which must be studied directly at the protein level. Understanding the basic systems biology of host-pathogen interactions will provide knowledge needed to ultimately develop rational 'systems therapy'for infectious diseases.